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BJO Online First, published on July 15, 2015 as 10.1136/bjophthalmol-2015-307157
Department of Ophthalmology,
Massachusetts Eye and Ear
Infirmary, Harvard Medical
School, Boston, Massachusetts,
USA
Correspondence to
Dr James Chodosh,
Department of Ophthalmology,
Massachusetts Eye and Ear
Infirmary, Howe Laboratory
Harvard Medical School, 243
Charles Street, Boston, MA
02114, USA; james_chodosh@
meei.harvard.edu
Received 14 May 2015
Revised 18 June 2015
Accepted 29 June 2015
To cite: Davies EC,
Langston DP, Chodosh J. Br
J Ophthalmol Published
Online First: [ please include
Day Month Year]
doi:10.1136/bjophthalmol-
2015-307157
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
Clinical science
Herpes zoster ophthalmicus: declining age
at presentation
Emma C Davies, Deborah P Langston, James Chodosh
ABSTRACT
Objective To investigate changes in the age of
occurrence of herpes zoster ophthalmicus (HZO) in
patients presenting to the Massachusetts Eye and Ear
Infirmary (MEEI) from 2007 through 2013.
Design Retrospective chart review.
Setting Academic tertiary referral centre for ophthalmic
conditions.
Participants 913 patients with acute HZO.
Methods A total of 1283 potential cases were
identified by searching the MEEI electronic medical
record for patient charts with International Classification
of Diseases 9 codes for herpes zoster, shingles and
varicella from 2007 through 2013. The cases were
reviewed to confirm diagnosis of acute HZO, requiring
documentation of a skin rash or pain in the V1
distribution, resulting in inclusion of 913 cases.
Main outcome measures Number of HZO cases
each year, mean age of HZO cases each year, number of
HZO cases with an immunodeficiency state.
Results The number of patients with HZO presenting
to MEEI increased from 71 cases in 2007 to 195 cases
in 2013. The mean age of patients with acute HZO
reduced significantly from 61.2 years in 2007 to
55.8 years in 2013 ( p=0.0119). The number of patients
with acute HZO in the setting of an immunodeficiency
state did not change significantly over the study period.
Conclusions Ever since the introduction of varicella
vaccination in children, there has been debate regarding
its effect on zoster epidemiology, particularly regarding
the potential to reduce population exposure and limit
repeated immunological boosts against varicella zoster
virus in adults. Patients presenting to MEEI with HZO
were younger on average in 2013 than in 2007.
Although a population-based study is necessary to test
the hypothesis, our study suggests that varicella
vaccination of children remains a possible explanation for
the increased number of cases and reduction in mean
age of newly diagnosed patients.
INTRODUCTION
Varicella zoster virus (VZV) causes varicella
(chickenpox) as a primary infection, and after
remaining latent within sensory ganglia, the virus
may reactivate to cause herpes zoster (shingles).
Herpes zoster ophthalmicus (HZO) is the reactiva-
tion of VZV involving the dermatomes supplied by
the first branch (V1) of the trigeminal nerve gan-
glion with ocular involvement. The ocular compli-
cations of HZO are many, and include acute and
postherpetic neuralgia, vesicular dermatitis and pre-
septal cellulitis, orbital cellulitis, epithelial keratitis
(including infectious corneal pseudodendrites),
stromal and endothelial keratitis, neurotrophic ker-
atopathy with or without ulceration, uveitis,
Davies EC, et al. Br J Ophthalmol 2015;0:1–3. doi:10.1136/bjophthalmol-2015-307157
glaucoma from trabeculitis, retinitis, choroiditis and
optic neuritis.1 2
Since the introduction of a universal childhood
vaccination programme for varicella, there has been
widespread debate about its impact on herpes zoster
epidemiology. In 1995, the USA became the first
country to mandate a one-dose childhood varicella
vaccination. The varicella vaccination programme
was, subsequently, expanded to a two-dose schedule
in 2006 due to insufficient population immunity
with just one dose.3 By 2006, national varicella
vaccine coverage among children aged 19–
35 months reached 89%, and this proportion of
vaccinated children has remained around 90% ever
since.4 During the same time period, varicella
disease morbidity and mortality declined by as
much as 80%–90%.5 Several studies have demon-
strated that repeat exposures to VZV boost immun-
ity in individuals with a history of varicella infection
and that this could prevent, minimise, or delay
development of herpes zoster.6–9 Based on these
findings, it has been hypothesised that the
vaccine-related reduction in varicella disease in the
USA would lead to fewer exposures and less
immune boosting within the adult population, and,
therefore, increase the incidence of herpes zoster.5–9
Furthermore, like wild-type VZV, vaccine strain
VZV can result in latent infection and reactivation,
suggesting that as the vaccinated paediatric popula-
tion ages, the cell-mediated immunity to the virus
will decline such that these patients can also develop
herpes zoster later on.10 11
In the USA, several studies from 1992 to 2010
have reported increased herpes zoster incidence
with time, except for one study,12 showed no evi-
dence of significant change in age of onset since
the varicella vaccination programme was intro-
duced.13–16 However, the short length of follow-up
after institution of the two-dose vaccination pro-
gramme in 2006 and the lack of data for a wide
array of age groups limit these studies.
The present study investigated the age and
number of newly diagnosed HZO cases in patients
who presented to the Massachusetts Eye and Ear
Infirmary (MEEI) for care from 2007 through
2013. We discuss changes in age at occurrence in
the context of a putative impact of the varicella
immunisation programme on HZO rates.
METHODS
Approval was obtained from the Institutional
Review Board of MEEI for this retrospective chart
review study. The screening process to determine
eligible subjects involved the search of the elec-
tronic medical record for all patient charts with
International Classification of Diseases 9 (ICD-9)
1
 Downloaded from http://bjo.bmj.com/ on September 16, 2016 - Published by group.bmj.com
Clinical science
diagnosis codes pertaining to herpes zoster, shingles and vari-
cella, including 053.9, 053.10, 053.13, 053.19, 053.20,
053.21, 053.22, 053.29, 053.71, 053.79, 053.80, 052.7, 052.8,
052.9, 054.3, 042 and V12.09 from 1 January 2007 (the onset
of electronic medical record use at MEEI) through 31
December 2013. A total of 1283 unique medical record
numbers were identified with at least one of these ICD-9 diag-
nosis codes. The medical records of potential patients with
herpes zoster were reviewed to confirm the diagnosis of acute
HZO and identify the date of disease onset. The criteria for
confirmation of the diagnosis of HZO included physician-
confirmed diagnosis with a skin rash and pain in the V1 distri-
bution or signs consistent with HZO such as pseudodendrites
or positive result on testing for VZV by PCR. The date and age
of the patient at the time of diagnosis were documented for
each case. The review resulted in 913 patients diagnosed with
HZO with or without ocular involvement ( patients without
ocular involvement had V1 distribution rash and pain only)
from 2007 through 2013 at MEEI.
The data were analysed to determine the total number of
cases of HZO per year as well as the age of presentation. A
linear regression model was fit to the data of number of cases
over time as well as mean patient age over time to determine
trends in presentation to our hospital. The number of patients
with acute HZO and an associated immunodeficiency state,
including HIV infection, lymphoma/leukaemia with reduced
white blood cell counts, organ transplant and chronic high-dose
corticosteroid use, were also quantified over the study period.
RESULTS
Of the 1283 medical records reviewed during this retrospective
chart review, 913 total cases of acute HZO were identified from
2007 through 2013. The remaining 370 medical records were
excluded for a variety of reasons, most commonly due to a diag-
nosis of past HZO ( patients who were diagnosed with acute
HZO prior to 2007, and were being followed for chronic HZO
complications during the study period) or an alternative diagno-
sis such as herpes simplex virus infection. Of the 913 total cases
of acute HZO, 311 cases (31.1%) had documented evidence of
ocular involvement.
The number of new cases of HZO per year at MEEI increased
from 71 in 2007 to 195 in 2013, despite a stable number of
new-patient clinic visits to MEEI between 2007 through 2013
(data not shown). Notably, all 913 patients were new to MEEI
at the time of presentation with HZO. Cases with acute onset
Figure 1 Scatter graph of number of acute herpes zoster
ophthalmicus (HZO) cases at Massachusetts Eye and Ear Infirmary each
year from 2007 through 2013 with line of best fit shown (R2=0.82).
2 Davies EC, et al. Br J Ophthalmol 2015;0:1–3. doi:10.1136/bjophthalmol-2015-307157
HZO increased over time in a linear fashion (R2=0.82) (figure
1). In contrast, the mean age of patients diagnosed with acute
HZO decreased significantly over time (R2=0.80, p=0.0119)
from 61.2 years (SD±12.9 years) in 2007 to 55.8 years (SD
±12.9) in 2013 (figure 2). The number of patients with acute
HZO and an associated immunodeficiency state presenting to
MEEI ranged from a maximum of five cases (2007, 2010) to a
minimum of two cases (2009, 2011, 2013).
DISCUSSION
The number of patients with acute HZO presenting to MEEI
increased from 2007 through 2013. Concurrently, the mean age
of all patients diagnosed with acute HZO declined. Although
we cannot estimate incidence rates without knowing the total
population served by MEEI in any given year, or the degree to
which referral patterns may have influenced the number of new
cases, these data support the notion that the epidemiology of
HZO may be changing.
One hypothesis for this observed increased occurrence of
acute HZO is that institution of the vaccine against primary
varicella infection in children has reduced the natural immuno-
logical boost granted to adults who come in contact with
infected children.5–9 A previous study of Medicare claims
demonstrated an increased incidence of herpes zoster in the
elderly population over the time period of 1992–2010.16
Medical claims data for a single herpes zoster ICD-9 code from
1993 to 2006 showed that herpes zoster incidence increased for
all age groups, and that the mean age of herpes zoster cases had
not changed over time.13 These studies concluded that since
herpes zoster incidence was increasing prior to the institution of
the two-dose childhood varicella vaccination programme in
2006, the varicella vaccination programme was not the cause.
These studies were limited by the lack of time for follow-up,
ranging from 0 to 4 years, after the institution of the varicella
vaccination programme. However, a recent study from Chan
et al12 analysed patients presenting to the University of
Oklahoma with HZO. Cases were stratified into two groups:
those presenting with HZO from 1996 to 2004 (n=130) or
from 2005 to 2012 (n=270). The authors showed a significant
decrease in mean age of HZO onset in the latter group (65.5 vs
58.9 years of age, respectively). Therefore, their study demon-
strates the same overall trend as in our analysis, with declining
age at HZO presentation over time.
Figure 2 Scatter graph of mean age of patients with acute herpes
zoster ophthalmicus at Massachusetts Eye and Ear Infirmary per year
from 2007 through 2013 with line of best fit shown (R2=0.80,
p=0.0119).
 Downloaded from http://bjo.bmj.com/ on September 16, 2016 - Published by group.bmj.com
A causal relationship between the institution of the two-dose
varicella vaccination programme in 2006 and an increased inci-
dence of herpes zoster and/or earlier age of onset would be diffi-
cult to test. The current project provides evidence that a greater
number of patients in the population served by MEEI sought
care for HZO since initiation of electronic medical record
keeping in 2007, but cannot determine the proportion of
patients in the overall population with new-onset HZO.
Notably, the total number of new patients seen at MEEI was
essentially unchanged between 2007 and 2013; so, the propor-
tion of new patients presenting with acute onset of HZO rela-
tive to the total number of new patients did increase.
The mean age of patients presenting with acute HZO to MEEI
appears to be declining. There are several potential explanations
for this finding. The first vaccine against herpes zoster was
approved and licensed by the US Federal Drug Administration in
2006 for people aged 60 years or older, and extended to people
aged 50–59 years in 2011.17 The Centers for Disease Control
recommends routine use of the zoster vaccination in patients
older than 60 years, but does not have a recommendation for
routine use of the vaccine in people aged 50–59 years.18 The
rates of vaccination in the USA have remained extremely low;
only 24.2% of eligible patients older than 60 years of age
received the vaccination in 2013.19–21 Therefore, the herpes
zoster vaccine is unlikely to explain the observed trend in age of
new-onset HZO. A national herpes zoster immunisation pro-
gramme started in England in 2013 to routinely vaccinate
patients aged 70 years or older.22 Although higher than in the
USA, overall coverage of the zoster vaccination programme in
England in February 2015 was only 48.7% in patients aged
70 years. An increased prevalence of immunosuppressed patients
could also explain a reduction in age of new HZO cases, but no
such trend was observed in our series. In fact, the occurrence of
an immunocompromised state in patients with HZO was rela-
tively rare throughout the study time period. Vaccination of chil-
dren against varicella can result in less natural varicella immune
boosting in the general population, and thereby increase the risk
of varicella reactivation (herpes zoster) at a younger age. Thus,
vaccination of children against varicella remains a possible
explanation for both the increased cases of HZO in all age
groups as well as the reduction in the mean age of patients with
HZO. Our data provides evidence to support the recommenda-
tion for vaccination against zoster for immunocompetent patients
aged 50 years or older.
The current study is limited by numerous factors outside the
authors’ control. For example, the number of years studied was
limited by the availability of electronic medical record coding.
Referral and presentation to MEEI may not represent an accur-
ate measure of disease incidence in the community. Such limita-
tions would have been difficult to avoid in this retrospective
chart review. Previous studies demonstrated an increasing inci-
dence of herpes zoster without a clear explanation for the
trend.13–16 The data presented herein are consistent with the
proposition that the combined increase in number of cases and
reduced mean age of HZO might be attributed at least in part
to the influence of varicella vaccination on the epidemiology of
herpes zoster.
Davies EC, et al. Br J Ophthalmol 2015;0:1–3. doi:10.1136/bjophthalmol-2015-307157
Clinical science
Contributors ECD, JC and DPL all made substantial contributions to the
conception of the work, acquisition and interpretation of data, drafting the work
and final approval of the version published. ECD, JC and DPL agree to be
accountable for all aspects of the work.
Funding This work was supported by the N&J Johnstone Fund, G Stevens Fund
and an unrestricted grant from Research to Prevent Blindness.
Competing interests None declared.
Ethics approval Mass. Eye and Ear Human Studies Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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3
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Herpes zoster ophthalmicus: declining age at

presentation
Emma C Davies, Deborah P Langston and James Chodosh

Br J Ophthalmol published online July 15, 2015

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